Breast Cancer, Breast Neoplasms
Conditions
Keywords
Breast Cancer, Breast Tumors, Cancer of Breast, Cancer of the Breast, Human Mammary Carcinoma, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Mammary Neoplasms, Human, Neoplasms, Breast, Tumors, Breast, Chloroquine, Paclitaxel, Taxol, Ixabepilone, Abraxane, Metastatic Breast Cancer, Advanced Breast Cancer, Anthracycline
Brief summary
The major purpose of this research study is to better understand how therapy works on different patients. This study is being offered to patients with a diagnosis of advanced or metastatic breast cancer who have failed anthracycline based therapy. The investigators want to see the response of breast cancer cell when treated with Chloroquine used in combination with chemotherapy. Chemotherapy is an anti-cancer drug that is given through your vein. The chemotherapy used in this study is either Taxane (Paclitaxel) or Taxane-like drugs (Abraxane, Ixabepilone or Docetaxel).
Detailed description
The purpose of this study is to determine the anti-tumor activity of the combination of Chloroquine combined with a Taxane or Taxane-like chemo agents(Paclitaxel, Docetaxel, Abraxane, Ixabepilone). The laboratories have developed robust preclinical models utilizing both in vitro systems such as the mammosphere (MS) culture and in vivo systems such as human breast cancer xenografts allowing the investigators to identify agents which selectively target TICs, as single agents or in combination. These models are critical since tumor initiating cells (TICs) comprise only a small percentage of the tumor bulk, so that clinical tumor regression may not be observed with inhibitors that selectively target TIC self-renewal alone. Nonetheless, these agents in combination with conventional therapy may effectively kill both actively cycling or fully differentiated cells and the TIC subpopulation, leading to long term remission and eradication of cancer cells.
Interventions
DRUGPaclitaxel
Chloroquine 250mg po daily together with Paclitaxel (Taxane) 175 mg/m2 three hours infusion every three weeks.
DRUGDocetaxel
Chloroquine 250mg po daily together with docetaxel 75 mg/m2 administered intravenously over one hour every three weeks
DRUGAbraxane
Chloroquine 250mg po daily together with Abraxane 260 mg/m2 administered intravenously over 30 minutes every three weeks.
DRUGIxabepilone
Chloroquine 250mg po daily together with Ixabepilone is 40 mg/m2 administered intravenously over three hours every three weeks.
Sponsors
The Methodist Hospital Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Females with pathologically determined advanced or metastatic breast cancer. 2. Have progressed after treatment with regimen that included an anthracycline. 3. Have had at least 4 cycles of an anthracycline containing regimen or 2 cycles if progressing on treatment. 4. Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors. 5. ≥18 years of age. 6. ECOG PS of 0, 1, or 2. 7. Laboratory values within the following ranges: * Hemoglobin ≥9.0gm/dL (≥1.5μmol/L); transfusions permitted. * Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L) * Platelet count ≥100,000/mm3 (100 x 109/L) * Creatinine (Cr) \<2 X the upper limit of normal (ULN), Cr clearance (CrCl) ≥30 by Cockcroft and Gault * Alanine aminotransferase and aspartate aminotransferase \<2 X the ULN; if liver metastases are present then must be \<5 X the ULN, Bilirubin \<2 X the ULN, Potassium within normal limits, Magnesium within normal limits 8. Negative serum pregnancy test at the time of first dose for women of childbearing potential (WOCBP). For WOCBP, adequate contraception must be used throughout the study. For this study, acceptable methods of contraception include a reliable intrauterine device or a spermicide in combination with a barrier method. Women who are already on hormonal forms of birth control may continue that treatment but must also use a barrier method. 9. Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments. 10. Patient must be willing to undergo breast biopsies as required by the study protocol.
Exclusion criteria
1. Radiation therapy within 2 weeks; or chemotherapy or non-cytotoxic investigational agents within 4 weeks of initiating study treatment. 2. Evidence of New York Heart Association class III or greater cardiac disease. 3. History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within 12 months. 4. History of congenital QT prolongation. 5. QT \>500. 6. Concurrent severe or uncontrolled medical disease (i.e., active systemic infection, diabetes, hypertension, coronary artery disease, congestive heart failure) that, in the opinion of the Investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study. 7. Symptomatic central nervous system metastases. The patient must be stable after radiotherapy for ≥2 weeks and off corticosteroids for ≥1 week. 8. Pregnant or nursing women. 9. Hypersensitivity or intolerance to Chloroquine, Paclitaxel, Docetaxel, Abraxane, Ixabepilone or other Taxane like drugs. 10. Severe renal insufficiency (CrCl \<30mL/min \[Cockcroft and Gault\]). 11. History of gastrointestinal bleeding, ulceration, or perforation. 12. Concurrent use of potent CYP3A4 inhibitors, such as ketoconazole, itraconazole,clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole. 13. Concurrent use of potent CYP3A4 inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbitol, and St. John's wort.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 3-week cycles for maximum of 6 cycles (4.5 months) | To determine the anti-tumor activity of the combination of Chloroquine + Taxane or Taxane-like chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) measured by overall Response Rate (ORR) defined as percentage of patients having complete or partial response in therapy per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. The study was designed to compare the ORR with the published percentage of 30% (docetaxel 100 mg/ml2 every 3 weeks for maximum of 10 cycles). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression Free Survival (PFS) | 25.4 months (median) | To assess the time to progression free survival of patients treated with the combination of Chloroquine and Taxane or Taxane-Like chemotherapy. Progression is defined as time from initiation of chemotherapy to disease progression using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate. |
| Time of Overall Survival (OS) | a median of 25.4 months, up to 83.5 months | To assess the time of overall survival of patients receiving Chloroquine + Taxane or Taxane-like chemotherapy |
| Number of Patients Who Experienced Grade 3 of Greater Adverse Events | 25.4 months (median) | To assess how many patients experienced grade 3 or greater adverse events when receiving the combination of Chloroquine and Taxane or Taxane-Like chemotherapy. Toxicity was assessed for all enrolled patients who received one or more doses of the study drug combination by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
Countries
United States
Participant flow
Recruitment details
38 patients were enrolled in the study and 31 patients were evaluated for response.
Participants by arm
| Arm | Count |
|---|---|
| Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy Chloroquine (250 mg) was given daily orally with either Paclitaxel or Docetaxel or Abraxane or Ixabepilone chemotherapy every 3 weeks (1 cycle) for a maximum of 6 cycles.
Paclitaxel: Chloroquine 250mg po daily together with Paclitaxel (Taxane) 175 mg/m2 three hours infusion every three weeks.
Docetaxel: Chloroquine 250mg po daily together with docetaxel 75 mg/m2 administered intravenously over one hour every three weeks
Abraxane: Chloroquine 250mg po daily together with Abraxane 260 mg/m2 administered intravenously over 30 minutes every three weeks.
Ixabepilone: Chloroquine 250mg po daily together with Ixabepilone is 40 mg/m2 administered intravenously over three hours every three weeks. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Toxicity | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy |
|---|---|
| Age, Continuous | 54.1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HR+ HEGFR- breast cancer | 20 Participants |
| Locally advanced breast cancer | 15 Participants |
| Metastatic breast cancer | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 38 Participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 0 Participants |
| Triple Negative Breast Cancer | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 31 |
| other Total, other adverse events | 9 / 38 |
| serious Total, serious adverse events | 1 / 38 |
Outcome results
Primary
Overall Response Rate (ORR)
To determine the anti-tumor activity of the combination of Chloroquine + Taxane or Taxane-like chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) measured by overall Response Rate (ORR) defined as percentage of patients having complete or partial response in therapy per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. The study was designed to compare the ORR with the published percentage of 30% (docetaxel 100 mg/ml2 every 3 weeks for maximum of 10 cycles).
Time frame: 3-week cycles for maximum of 6 cycles (4.5 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy | Overall Response Rate (ORR) | 45.16 percentage of participants |
Secondary
Number of Patients Who Experienced Grade 3 of Greater Adverse Events
To assess how many patients experienced grade 3 or greater adverse events when receiving the combination of Chloroquine and Taxane or Taxane-Like chemotherapy. Toxicity was assessed for all enrolled patients who received one or more doses of the study drug combination by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: 25.4 months (median)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy | Number of Patients Who Experienced Grade 3 of Greater Adverse Events | 4 Participants |
Secondary
Time of Overall Survival (OS)
To assess the time of overall survival of patients receiving Chloroquine + Taxane or Taxane-like chemotherapy
Time frame: a median of 25.4 months, up to 83.5 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy | Time of Overall Survival (OS) | 25.4 months |
Secondary
Time to Progression Free Survival (PFS)
To assess the time to progression free survival of patients treated with the combination of Chloroquine and Taxane or Taxane-Like chemotherapy. Progression is defined as time from initiation of chemotherapy to disease progression using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate.
Time frame: 25.4 months (median)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chloroquine With Taxane or Taxane-Like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) Chemotherapy | Time to Progression Free Survival (PFS) | 12.4 months |